hc-030031 and Facial-Pain

This study aimed to evaluate the antinociceptive effect of oleanolic acid using adult zebrafish models of orofacial pain. Acute nociception was induced by formalin, capsaicin, cinnamaldehyde, menthol, acidified saline or glutamate (cutaneous modes) and hypertonic saline (corneal model). In another set of experiments, animals were pre-treated with naloxone, L-NAME, methylene blue, ketamine, camphor, HC-030031, mefenamic acid, ruthenium red or amiloride to investigate the mechanism of antinociception. The involvement of central afferent C-fibers was also investigated. A molecular docking was performed using the TRPV1 channel. Motor activity was evaluated with the open field test. Pre-treatment with oleanolic acid significantly reduced nociceptive behavior associated with acute pain. Antinociception was effectively inhibited by ruthenium red and capsaicin-induced desensitization. Presence of trpv1 was confirmed by RT-PCR in cerebral tissue of zebrafish. In line with in vivo experiments, docking studies indicated that oleanolic acid may interact with TRPV1. Results confirm the potential pharmacological relevance of oleanolic acid as an inhibitor of orofacial nociception mediated by TRPV1.

Topics: Acetanilides; Analgesics; Animals; Behavior, Animal; Binding Sites; Capsaicin; Facial Pain; Formaldehyde; Molecular Docking Simulation; Oleanolic Acid; Protein Structure, Tertiary; Purines; Ruthenium Red; Thermodynamics; TRPV Cation Channels; Zebrafish; Zebrafish Proteins

Thermal and mechanical hypersensitivity in the injured region is a common complication. Although it is well known clinically that thermal and mechanical sensitivity of the oral mucosa is different from that of the skin, the mechanisms underlying injured pain of the oral mucosa remain poorly understood. The transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) in primary afferent neurons are known to contribute to pathological pain. Therefore, we investigated whether TRPV1 and/or TRPA1 contribute to thermal and mechanical hypersensitivity following oral mucosa or whisker pad skin incision. Strong heat and mechanical and cold hypersensitivity was caused in the buccal mucosa and whisker pad skin following incisions. On day 3 after the incisions, the number of TRPV1-immunoreactive (IR) and TRPA1-IR trigeminal ganglion (TG) neurons innervating the buccal mucosa and whisker pad skin was significantly increased, and the number of TRPV1/TRPA1-IR TG neurons innervating whisker pad skin, but not the buccal mucosa, was significantly increased. Administration of the TRPV1 antagonist, SB366791, to the incised site produced a significant suppression of heat hyperalgesia in both the buccal mucosa and whisker pad skin, as well as mechanical allodynia in the whisker pad skin. Administration of the TRPA1 antagonist, HC-030031, to the incised site suppressed mechanical allodynia and cold hyperalgesia in both the buccal mucosa and whisker pad skin, as well as heat hyperalgesia in the whisker pad skin. These findings indicate that altered expressions of TRPV1 and TRPA1 in TG neurons are involved in thermal and mechanical hypersensitivity following the buccal mucosa and whisker pad skin incision. Moreover, diverse changes in the number of TRPV1 and TRPA1 coexpressed TG neurons in whisker pad skin-incised rats may contribute to the intracellular interactions of TRPV1 and TRPA1 associated with whisker pad skin incision, whereas TRPV1 and TRPA1 expression in individual TG neurons is involved in buccal mucosa-incised pain.

Topics: Acetanilides; Anilides; Animals; Cinnamates; Cold Temperature; Electromyography; Facial Pain; Hot Temperature; Hyperalgesia; Male; Mouth Mucosa; Neurons; Pain; Purines; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion; TRPA1 Cation Channel; TRPC Cation Channels; TRPV Cation Channels; Vibrissae

Orofacial cold hyperalgesia is known to cause severe persistent pain in the face following trigeminal nerve injury or inflammation, and transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankylin 1 (TRPA1) are thought to be involved in cold hyperalgesia. However, how these two receptors are involved in cold hyperalgesia is not fully understood. To clarify the mechanisms underlying facial cold hyperalgesia, nocifensive behaviors to cold stimulation, the expression of TRPV1 and TRPA1 in trigeminal ganglion (TG) neurons, and TG neuronal excitability to cold stimulation following facial capsaicin injection were examined in rats. The head-withdrawal reflex threshold (HWRT) to cold stimulation of the lateral facial skin was significantly decreased following facial capsaicin injection. This reduction of HWRT was significantly recovered following local injection of TRPV1 antagonist as well as TRPA1 antagonist. Approximately 30% of TG neurons innervating the lateral facial skin expressed both TRPV1 and TRPA1, and about 64% of TRPA1-positive neurons also expressed TRPV1. The TG neuronal excitability to noxious cold stimulation was significantly increased following facial capsaicin injection and this increase was recovered by pretreatment with TRPA1 antagonist. These findings suggest that TRPA1 sensitization via TRPV1 signaling in TG neurons is involved in cold hyperalgesia following facial skin capsaicin injection.

Topics: Acetanilides; Anilides; Animals; Behavior, Animal; Capsaicin; Cinnamates; Cold Temperature; Electromyography; Face; Facial Pain; Hot Temperature; Hyperalgesia; Injections, Intradermal; Male; Neural Conduction; Neurons; Physical Stimulation; Purines; Rats; Rats, Sprague-Dawley; Reflex; Sensory System Agents; Synaptic Transmission; Trigeminal Ganglion; TRPA1 Cation Channel; TRPC Cation Channels; TRPV Cation Channels